What are the presentation, symptoms, diagnosis, and treatment of Still's disease?

Still's Disease: Presentation, Symptoms, Diagnosis, and Treatment

Clinical Presentation

Still's disease (encompassing both systemic juvenile idiopathic arthritis and adult-onset Still's disease) presents with a characteristic triad of high spiking fever, salmon-pink evanescent rash, and musculoskeletal involvement, though arthritis is not required for diagnosis. 1

Cardinal Features

Fever:

• Spiking pattern with temperature ≥39°C (102.2°F) lasting at least 7 days 1
• Typically quotidian or double quotidian pattern, peaking in late afternoon or early evening 1
• Present in approximately 95.7% of patients 1, 2
• Episodes last typically under 4 hours 1

Rash:

• Salmon-pink, evanescent maculopapular eruption occurring in 51-87% of patients 1, 2
• Transient and often coincides with fever spikes 1
• Predominantly affects proximal limbs and trunk, rarely involving face and distal limbs 1
• May be mildly pruritic and confused with drug allergy 1
• Koebner phenomenon has been described 1

Musculoskeletal Involvement:

• Arthralgia/myalgia present in the majority of patients 1
• Overt arthritis is supportive but NOT necessary for diagnosis and may appear later (median delay of 1 month, range 0 to several months) 1
• When arthritis develops, most commonly affects knees (82%), wrists (73%), and ankles (55%) 1
• Carpal and pericapitate abnormalities typically appear 6 months after disease onset 1
• Pattern is typically symmetric polyarthritis associated with fever spikes 1

Additional Clinical Manifestations

• Sore throat/pharyngitis: 35-92% of patients 1, 2
• Myalgia: 56-84% of patients 1, 2
• Lymphadenopathy: 32-74% of patients 1, 2
• Splenomegaly: 14-65% of patients (average ~32%) 1, 2
• Serositis:
  • Pericarditis: 10-37% of patients 1, 2
  • Pleuritis: 12-53% of patients 1, 2

Diagnosis

Operational Definitions for Rapid Diagnosis

The 2024 EULAR/PReS guidelines provide specific operational definitions to facilitate early diagnosis: 1

1. Fever: Spiking temperature ≥39°C (102.2°F) for at least 7 days
2. Rash: Transient, erythematous (salmon pink), coinciding with fever spikes, preferentially involving trunk
3. Musculoskeletal: Arthralgia/myalgia present; arthritis supportive but NOT mandatory
4. Inflammation: Neutrophilic leukocytosis, elevated ESR, CRP, and ferritin

Laboratory Findings

Characteristic laboratory abnormalities include: 1

• Leukocytosis: Often >15×10⁹/L with striking neutrophilia; 50% have counts >15×10⁹/L, 37% have >20×10⁹/L 1
• Elevated acute phase reactants: ESR and CRP raised in virtually all patients 1
• Markedly elevated ferritin: Key diagnostic marker 1
• Anemia: Normocytic normochromic anemia of chronic disease 1, 3
• Thrombocytosis: Reactive thrombocytosis common 1
• Negative serology: Rheumatoid factor and antinuclear antibodies characteristically negative 1, 3

Novel biomarkers that strongly support diagnosis (measure if available): 1

• Marked elevation of serum IL-18
• Elevated S100 proteins (e.g., calprotectin)

Diagnostic Criteria

The Yamaguchi criteria are most widely used and validated in both children and adults with high sensitivity: 1, 4

• Major criteria: Fever, arthralgia, typical rash, leukocytosis 2
• Minor criteria: Sore throat, lymphadenopathy/splenomegaly, liver dysfunction, negative RF and ANA 2

Critical diagnostic principle: Arthritis is NOT mandatory for diagnosis in Yamaguchi criteria or recent classification criteria, as requiring arthritis leads to unnecessary and potentially deleterious diagnostic delays. 1

Differential Diagnosis

Alternative diagnoses must be carefully excluded: 1

• Malignancies (especially lymphoma and leukemia) 3
• Infectious diseases
• Other immune-mediated inflammatory diseases
• Monogenic autoinflammatory disorders

Treatment

Treatment Principles

The ultimate goal is drug-free remission, achieved through a treat-to-target (T2T) approach with regular disease activity assessment and dynamic therapy adjustment. 1

First-Line Treatment

IL-1 inhibitors (anakinra) or IL-6 receptor inhibitors (tocilizumab) should be initiated as early as possible when diagnosis is established, as these biologics show the highest level of evidence for efficacy and safety. 1, 5

This represents a paradigm shift from historical management, as:

• NSAIDs are effective as monotherapy in only 7-15% of patients 5
• Glucocorticoids, while historically the mainstay (76-95% response rates), require long-term maintenance with significant side effects 5
• Conventional DMARDs (particularly methotrexate) have modest efficacy (~40% overall response) 5

Treatment Targets and Timeline

Specific intermediate targets to achieve drug-free remission: 1

• Day 7: Resolution of fever and CRP reduction by >50%
• Week 4: No fever, active joint count reduction by >50%, normal CRP, physician and patient global assessment <20 on 0-100 VAS
• Month 3: Clinically inactive disease (CID) with glucocorticoids <0.1-0.2 mg/kg/day
• Month 6: CID without glucocorticoids

CID is defined as absence of Still's disease-related symptoms and normal ESR or CRP. Remission is defined as at least 6 months with CID. 1

Maintain CID for 3-6 months without glucocorticoids before initiating biologic DMARD tapering. 1

Management of Refractory Disease

If no response to initial biologic therapy, rotating between IL-1 and IL-6 inhibitors may be considered. 5

Difficult-to-treat patients should be managed in collaboration with Still's disease expert centers. 1

Life-Threatening Complications

Macrophage Activation Syndrome (MAS)

MAS is the most challenging and life-threatening complication, requiring prompt detection and rapid treatment. 1

Clinical features suggesting MAS: 1

• Persistent fever
• Splenomegaly
• Elevated or rising serum ferritin
• Inappropriately low cell counts (pancytopenia)
• Abnormal liver function tests
• Intravascular activation of coagulation
• Elevated or rising serum triglycerides

MAS treatment must include: 1, 5

• High-dose glucocorticoids (mandatory)
• Anakinra (high-dose: >4 mg/kg/day in children or 100 mg twice daily in adults)
• Consider ciclosporin and/or IFN-γ inhibitors as part of initial therapy

Critical pitfall: MAS can occur at disease onset, during treatment, or even during remission, especially in context of infection. Physicians must always be aware of this risk and monitor with adequate biological workups. 1

Lung Disease

Active screening for lung disease is essential: 1

• Search for clinical symptoms: clubbing, persistent cough, shortness of breath
• Pulmonary function tests: pulse oximetry, DLCO measurement
• High-resolution CT scan in any patient with clinical symptoms

Important: The presence of risk factors for Still's lung disease or development of lung disease should NOT be considered a contraindication to IL-1 or IL-6 inhibitors. 1

Disease Course Patterns

Still's disease typically follows one of three clinical patterns, each affecting approximately one-third of patients: 2, 5

1. Self-limited/monocyclic: Systemic symptoms with remission within 1 year (median 9 months)
2. Intermittent/polycyclic: Recurrent flares with complete remission between episodes
3. Chronic articular: Dominated by joint manifestations that can lead to severe joint destruction

Patients with chronic articular disease generally have worse prognosis and may require more aggressive therapy. 5